HIV infection of children results in a higher incidence of neurologic disease than is seen in adults To explore the pathogenesis of neonatal infection of the CNS, we examined 20 rhesus macaque neonates inoculated intravenously with SIV within 24 hours of birth The viral inocula included the pathogenic molecular clone SIVmac239 (n = 13), the macrophage-competent derivative SIVmac239/316 (n = 2), the minimally pathogenic SIVmac239 nef (n = 2) and uncloned SIVmac251 (n = 3) Infected neonates were sacrificed at intervals over the first 50 days (n = 16) or allowed to progress to terminal disease (n =4) Viral DNA was detected in the brain by nested PCR for gag by day 3 and viral RNA was detected by radiolabeled in situ hybridization (ISH) by day 7 Histologic changes in the brain were limited to mild perivascular infiltrates of mononuclear cells and focal mineralization of vessels in the basal ganglia Cells positive for SIV by ISH were occasionally associated w ith vessels and found most often in the cortical gray matter and basal ganglia In addition, many infected cells were scattered throughout the parenchyma without any associated histologic lesions In total, 8/13 SIVmac239-, 1/2 SIVmac239/316-, 2/3 SIVmac251- and 0/2 SIVmac239 nef-infected neonates had virus detected in the CNS by ISH However, the number of infected cells was low and virus was not detectable by immunohistochemistry or nonradiolabeled ISH In contrast to the limited infection of the CNS these same animals (excluding those inoculated with SIVmac239 nef) had high viral loads in peripheral blood and abundant virus in lymphoid organs Furthermore, the number of infected cells in the CNS was much less than that observed previously in adult macaques inoculated with the same dose and stock of virus Thus, while neuroinvasion by these stocks of SIV in neonates is comparable to that observed in older animals, the number of infected cells and severity of lesions was limited T his may be related to the abundance of CD4+ T cells in the periphery of neonates and a relative paucity of infection of monocyte/macrophages evident by combined in situ hybridization/immunohistochemistry